Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a progressive, fatal neurological disease affecting as many as 30,000 Americans, with 5,000 new cases occurring in the United States each year. In ALS, the motor neurons in the brain and spinal cord that control voluntary movement degenerate over time. The loss of these motor neurons causes the muscles under their control to weaken and waste away, leading to paralysis and death. The mean survival time for ALS patients is 2-5 years post-diagnosis. ALS typically strikes in mid-life, and men are about one-and-a-half times more likely to develop the disease than women. There is no cure for ALS, and present therapies provide only supportive care during the inevitable decline of the patient.
ALS occurs in both sporadic (SALS) and familial (FALS) forms. Recent genetic and biochemical studies implicate free radical toxicity and glutamate excitotoxicity as possible causes of SALS. About 10% of all ALS patients are familial cases, of which 20% have mutations in the superoxide dismutase 1 (SOD1) gene (formerly known as Cu, Zn-SOD). An abnormally functioning SOD1 enzyme may therefore play a pivotal role in the pathogenesis and progression of FALS (Rosen et al., 1993, Nature 362: 59; Siddique et al., 1991, N. Engl. J. Med. 324:1381).
More than 50 point mutations of the human SOD1 gene have been found in patients with FALS. Most of the mutations occur at regions which encode the SOD1 active site, so that the enzymes produced from the mutant SOD1 genes have reduced activity. The function of the SOD1 enzyme is to remove oxygen radicals from the cellular environment. Motor neurons which produce mutant SOD1 therefore show increased oxygen radical generation. It is believed that the increased generation of oxygen free radicals, especially hydroxyl radicals, due to the presence of mutant SOD1 triggers in the sequence of events leading to motor neuron death in FALS. This hypothesis is supported by recent reports that transfection of neuronal precursor cells with mutant SOD1 results in increased production of hydroxyl radicals and enhanced rate of cell death by apoptosis (Liu et al., 1999, Radiat. Res. 151:133).
The only approved drug for treatment of ALS is the glutamate-release antagonist riluzole, which extends the lifespan of ALS patients only by approximately 3 months. Thus, riluzole provides only a mild benefit to ALS patients. Moreover, riluzole evokes hepatic stress upon elevation of liver enzymes. It is poorly tolerated by a majority of patients.
The antibiotic minocycline has been reported to delay the onset and slow the progression of ALS symptoms in the “SOD1” mouse model of ALS, apparently by inhibiting apoptotic cell death in motor neurons. However, the effect of minocycline on SOD1 mouse survival is roughly equivalent to that of riluzole. Therefore, minocycline is not expected to significantly lessen ALS symptoms or lengthen the lifespan of ALS patients.
Clinical trials are underway to determine whether administration of creatine monohydrate increases muscle strength in ALS patients, and to determine whether insulin-like growth factor-1 (IGF-I) slows the progressive weakness in ALS patients. However, regulatory approval of these drugs for treatment of ALS is many years away, and in any case neither of these drugs are expected to provide more than a palliative effect.
What is needed, therefore, is a method of treating ALS which results in a reduction or reversal of symptoms, which significantly lengthens the lifespan of ALS patients, and which uses materials currently available for use in treatment of humans.